CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring <i>NRG1</i> fusions.
Authors: Daniel R. Carrizosa, Mark E. Burkard, Yasir Y Elamin, Jayesh Desai, Shirish M. Gadgeel, Jessica Jiyeong Lin, Saiama Naheed Waqar, David R. Spigel, Young Kwang Chae, Parneet K. Cheema, Eric B. Haura, Stephen V. Liu, Danny Nguyen, Karen L. Reckamp, Frank Yung-Chin Tsai, Valerie Malyvanh Jansen, Alexander E. Drilon, Sai-Hong Ignatius Ou, D. Ross Camidge, Tejas Patil
Journal: Journal of Clinical Oncology (2022)

3006 Background: NRG1 fusions are rare oncogenic drivers found in ̃0.2% of all solid tumors. These fusions elicit ERBB3/HER3 overactivation to drive tumor growth and cancer cell survival. Currently there are no approved targeted therapies for NRG1 fusion-positive tumors. Furthermore, patients (pts) with tumors harboring NRG1 fusions have poor outcomes with standard therapies. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that suppressed tumor growth in NRG1 fusion-driven preclinical models. Here, we present initial clinical data from the CRESTONE study (NCT04383210). Methods: CRESTONE is a Phase 2, global, multicenter, open-label study of seribantumab in adult pts with locally advanced or metastatic solid tumors harboring NRG1 fusions. A dose ranging phase established the RP2D as a 3g once weekly (QW) intravenous dose administered until treatment discontinuation criteria are met. In the expansion phase, cohort 1 will enroll at least 55 pts who had received at least one prior therapy and are naïve to ERBB-targeted therapy. Exploratory cohorts 2 or 3 will enroll pts previously treated with ERBB-targeted therapies and/or tumors harboring additional molecular alterations. The primary endpoint is objective response rate (ORR) by independent central review per RECIST v1.1. Initial data from cohort 1 pts who received seribantumab 3g QW with investigator (INV)-assessed response per RECIST v1.1 are reported. Results: By JAN-13-2022, 12 pts have received seribantumab 3g QW in cohort 1. Median age was 65 years (range 44–76), 67% were female, and median number of prior therapies was 1 (range 1–5). 92% (11/12) of pts had non-small cell lung cancer (NSCLC); 5 different NRG1 fusion partners ( ATP1B1, CD74, ITG B1, SDC4, SLC3 A2) were reported by local next-generation sequencing tests. Among 10 pts evaluable for INV-assessed response, the confirmed ORR was 30%, and the disease control rate was 90% (1 complete response, 2 partial responses, 6 stable disease, 1 progressive disease). 58% (7/12) of pts remain on study treatment, including 2 pts with NSCLC who achieved objective responses with an ongoing duration of response of 6 and 8.5 months. Seribantumab 3g QW was well tolerated with no drug discontinuations or dose reductions. Across all cohorts (n = 29), the most frequently (≥20%) reported treatment-related adverse events (TRAEs) were diarrhea (38%), fatigue (34%), and rash (24%), all were grade 1 or 2. One grade 3 TRAE of vomiting occurred; there were no Grade 4 or 5 TRAEs. Efficacy analysis is ongoing and updated efficacy data from evaluable pts in cohort 1 will be presented. Conclusions: Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions and has a favorable safety profile. These data support the continued evaluation of seribantumab in NRG1 fusion-positive solid tumors in the ongoing CRESTONE study. Clinical trial information: NCT04383210.